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School of Medicine
Janice Clements of Molecular and Comparative Pathobiology on how HIV infects the brain:
How did you become interested in studying viruses?
CLEMENTS: I went to graduate school at the University of Maryland to study biochemistry of cells in the brain. My first postdoc was with biochemist Bernard Weiss at Johns Hopkins in molecular biology and genetics. I always had an interest in the brain from a very molecular level, but I had not studied the nervous system. I did a second postdoctoral fellowship with Richard T. Johnson, who was the leader in virus infections of the brain and in the Department of Neurology here at Johns Hopkins.
In the late 1970s, we were studying this strange virus that infected sheep, Visna virus, which caused a disease that was similar to multiple sclerosis. The Visna virus got into the brain and caused a focused, inflammatory infection, and degrades myelin, the conducting material that helps signals pass along neurons, around the infected region. The Visna virus is a type of lentivirus made of RNA. I cloned the virus to study the viral genome and how this virus infected sheep. In the late 70s, I joined the faculty.
How did you transition to studying HIV?
CLEMENTS: AIDS was described in 1981 as an unusual viral infection that caused immunodeficiency and not only targeted the T cells in the blood, but targeted the brain too. Robert Gallo, at the NIH, who now is head of the HIV Institute at the University of Maryland, contacted us because he thought that the virus that caused AIDS might be a lentivirus because of its characteristics of causing prolonged infection that eventually lead to the death of the infected individual or animal. At the time, we were the only group with molecular experience in lentivirus research, so we shared our reagents with him and we confirmed that HIV was more closely related to lentiviruses than other viruses. That led us to study HIV, since we were already studying other lentiviruses, and I was interested in viruses that affected the brain.
In the early 80s, as HIV emerged as the virus that caused AIDS, there was a report of an AIDS-like virus in monkeys called simian immunodeficiency virus (SIV) that was shown to be the progenitor to HIV. So we decided to study the animal model and in particular study how the virus got into the brain, infected the brain and caused central nervous system disease.
When I think of HIV infection and AIDS, I think of problems with the immune system and I don’t associate it with affecting the nervous system. How prominent of a problem is HIV dementia?
CLEMENTS: The first HIV-infected patient at Hopkins in the early 80s showed signs of dementia and was treated by my mentor, Dr. Johnson. At that time, before HIV antiviral treatments were developed, 30 to 40 percent of people that developed AIDS also developed dementia. Dementia is a terrible condition that destroys the cognitive abilities of the patients and leaves them bed-ridden.
Now the cognitive effects of HIV are called HIV-associated neurocognitive disorders (HAND) and include dementia. With the advent of HAART (highly active antiretroviral therapy) for the treatment of HIV, fewer people develop full-blown AIDS, but the treatment doesn’t prevent HAND since the drug can’t get in the brain to stop the virus from doing damage.
You’ve been in the HIV field almost since the very beginning. What have you learned about HIV infection over the years?
CLEMENTS: As a molecular virologist, I characterized the molecular elements of infection in the brain. I showed how the HIV got into the brain by infecting macrophages—white blood cells that travel throughout the body and survey for infections. I showed what pieces of the proteins in the viral coat, the outer layer of the virus surrounding its genome, were important for infection. Proteins on the virus bind to CD4, a protein on immune cells, which most of the viruses use to get into to the cell. But, the CD4 protein is actually at low levels in the brain, and our lab discovered that the viruses that infected the brain used the cell surface protein CCR5 without requiring CD4. SIV and some strains of HIV can adapt and infect cells that do not have CD4, which is important because it shows how the virus adapts. If it can’t use one way to get into cells then it uses another one. HIV and all the lentiviruses are very adaptable to the host and evade the host defenses, resulting in inevitable disease progression and death.
--Interviewed by Vanessa McMains
Janice Clements on the discovery of minocycline for treating HIV-related cognitive disorders: